Molecular Architecture of a Sodium Channel S6 Helix

Yang, Yang; Estacion, Mark; Dib‐Hajj, Sulayman D.; Waxman, Stephen G.

doi:10.1074/jbc.m113.462366

Cited by 21 publications

(18 citation statements)

References 40 publications

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“…Modeling of Na v 1.7 also indicates that this residue contributes to the activation gate (Lampert et al, 2008; Yang et al, 2013). The Δ1750 mutation would move this residue into the membrane, substantially altering the geometry of the activation gate of Na v 1.6.…”

Section: Discussionmentioning

confidence: 97%

“…Nucleotides c.5248–5250 were deleted from the tetrodotoxin (TTX)-resistant derivative of the murine Na V 1.6 cDNA clone Na V 1.6R by site directed mutagenesis as previously described (Tyrrell et al, 2001; Lampert et al, 2008; Yang et al, 2013). The neuron-derived cell line ND7/23 was co-transfected with the Na v 1.6 cDNA and an eGFP cDNA using Lipofectamine 2000 (Invitrogen, Carlsbad, CA) as previously described (Sharkey et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

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Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder

Jones

Dionne

Dell’Orco

et al. 2016

Neurobiology of Disease

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Mutations of the neuronal sodium channel gene SCN8A are associated with lethal movement disorders in the mouse and with human epileptic encephalopathy. We describe a spontaneous mouse mutation, Scn8a 9J, that is associated with a chronic movement disorder with early onset tremor and adult onset dystonia. Scn8a 9J homozygotes have a shortened lifespan, with only 50% of mutants surviving beyond 6 months of age. The 3 bp in-frame deletion removes 1 of the 3 adjacent isoleucine residues in transmembrane segment DIVS6 of Nav1.6 (p.Ile1750del). The altered helical orientation of the transmembrane segment displaces pore-lining amino acids with important roles in channel activation and inactivation. The predicted impact on channel activity was confirmed by analysis of cerebellar Purkinje neurons from mutant mice, which lack spontaneous and induced repetitive firing. In a heterologous expression system, the activity of the mutant channel was below the threshold for detection. Observations of decreased nerve conduction velocity and impaired behavior in an open field are also consistent with reduced activity of Nav1.6. The Nav1.6Δ1750 protein is only partially glycosylated. The abundance of mutant Nav1.6 is reduced at nodes of Ranvier and is not detectable at the axon initial segment. Despite a severe reduction in channel activity, the lifespan and motor function of Scn8a9J/9J mice are significantly better than null mutants lacking channel protein. The clinical phenotype of this severe hypomorphic mutant expands the spectrum of Scn8a disease to include a recessively inherited, chronic and progressive movement disorder.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder

Jones

Dionne

Dell’Orco

et al. 2016

Neurobiology of Disease

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“…Structural modeling was performed as described previously (Yang et al, , 2013a. Briefly, sequence alignment was achieved using ClustalW2 and manually refined (Yarov-Yarovoy et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

“…1B). To visualize Ala1632Gly in the folded channel, we constructed a Nav1.7 structural model (Yang et al, , 2013a (Fig. 1C) and observed that Ala1632 is positioned at the turn between the S4-S5 linker and the S5 helix of domain IV (Fig.…”

Section: Clinical Description and Molecular Geneticsmentioning

confidence: 99%

“…Thus far, IEM mutations of Nav1.7 have been functionally assessed in several ways: (1) voltage-clamp recording permits an evaluation of the effects of the mutations on channel function (Cummins et al, 2004;Yang et al, 2013a); and (2) at a higher integrative level, current-clamp recording and dynamic clamp permit an assessment of the effects of the mutant channels on excitability of neurons carrying the mutant channels Rush et al, 2006;Han et al, 2012;Vasylyev et al, 2014). Currentclamp and dynamic clamp assessment, however, involve patchclamp recording, which entails perfusion of the cells under study.…”

Section: Introductionmentioning

confidence: 99%

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Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli

Yang¹,

Huang²,

Mis³

et al. 2016

Journal of Neuroscience

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Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we have studied a newly identified Nav1.7 mutation, Ala1632Gly, from a multigeneration family with IEM. Structural modeling suggests that Ala1632 is a molecular hinge and that the Ala1632Gly mutation may affect channel gating. Voltage-clamp recordings revealed that the Nav1.7-A1632G mutation hyperpolarizes activation and depolarizes fastinactivation, both gain-of-function attributes at the channel level. Whole-cell current-clamp recordings demonstrated increased spontaneous firing, lower current threshold, and enhanced evoked firing in rat DRG neurons expressing Nav1.7-A1632G mutant channels. Multielectrode array recordings further revealed that intact rat DRG neurons expressing Nav1.7-A1632G mutant channels are more active than those expressing Nav1.7 WT channels. We also showed that physiologically relevant thermal stimuli markedly increase the mean firing frequencies and the number of active rat DRG neurons expressing Nav1.7-A1632G mutant channels, whereas the same thermal stimuli only increase these parameters slightly in rat DRG neurons expressing Nav1.7 WT channels. The response of DRG neurons expressing Nav1.7-A1632G mutant channels upon increase in temperature suggests a cellular basis for warmth-triggered pain in IEM.

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Cumulative hydropathic topology of a voltage‐gated sodium channel at atomic resolution

et al. 2020

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Voltage‐gated sodium channels (NavChs) are biological pores that control the flow of sodium ions through the cell membrane. In humans, mutations in genes encoding NavChs can disrupt physiological cellular activity thus leading to a wide spectrum of diseases. Here, we present a topological connection between the functional architecture of a NavAb bacterial channel and accumulation of atomic hydropathicity around its pore. This connection is established via a scaling analysis methodology that elucidates how intrachannel hydropathic density variations translate into hydropathic dipole field configurations along the pore. Our findings suggest the existence of a nonrandom cumulative hydropathic topology that is organized parallel to the membrane surface so that pore's stability, as well as, gating behavior are guaranteed. Given the biophysical significance of the hydropathic effect, our study seeks to provide a computational framework for studying cumulative hydropathic topological properties of NavChs and pore‐forming proteins in general.

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Molecular Architecture of a Sodium Channel S6 Helix

Cited by 21 publications

References 40 publications

Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder

Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder

Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli

Cumulative hydropathic topology of a voltage‐gated sodium channel at atomic resolution

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